RESUMEN
The acyloxyalkyl derivatives of a model anti-HBV dinucleotide were synthesized and evaluated as orally bioavailable prodrugs. Our studies have led to the identification of the first orally bioavailable dinucleotide prodrugs for further therapeutic development against the hepatitis B virus (HBV).
Asunto(s)
Antivirales/química , Virus de la Hepatitis B/genética , Hepatitis B/tratamiento farmacológico , Nucleótidos/química , Profármacos/química , Administración Oral , Animales , Antivirales/síntesis química , Antivirales/uso terapéutico , Línea Celular , Femenino , Humanos , Masculino , Ratones , Ratones Transgénicos , Mutación , Nucleótidos/síntesis química , Nucleótidos/uso terapéutico , Profármacos/síntesis química , Profármacos/uso terapéutico , Ratas , Ratas Sprague-DawleyRESUMEN
The year 2002 marked the 20th anniversary of the first successful product of modern biotechnology, the regulatory approval of recombinant insulin for biopharmaceutical applications. Insulin is also the first crystalline protein to be approved for therapeutic use. Over the past two decades, almost 150 biopharmaceuticals have gained marketing authorisation; however, insulin remains the only crystalline protein on the market. Significant research and development efforts have focused on the engineering of protein molecules, efficacy testing, model development, and protein production and characterisation. These advances have dramatically boosted the therapeutic applications of proteins, which now include treatments against acute conditions, such as cancer, cardiovascular disease and viral disease, and chronic conditions, such as diabetes, growth hormone deficiency, haemophilia, arthritis, psoriasis and Crohn's disease. Despite these successes, many challenges normally associated with biopharmaceuticals, such as poor stability and limited delivery options, remain. Protein crystals have shown significant benefits in the delivery of biopharmaceuticals to achieve high concentration, low viscosity formulation and controlled release protein delivery. This review will discuss challenges related to the broader utilisation of protein crystals in biopharmaceutical applications, as well as recent advances and valuable new directions that protein crystallisation-based technologies present.